Project Summary Age-related macular degeneration (AMD), the leading cause of irreversible vision impairment in the US and third globally, is a disease of the photoreceptor support system involving the retinal pigment epithelium (RPE), Bruch's membrane, and the choriocapillaris, ultimately leading to photoreceptor demise and eventual vision loss. Our research with that of others has clearly documented the selective vulnerability of rod photoreceptors and rod-mediated (scotopic) vision, including delayed rod-mediated dark adaptation (RMDA) and impaired rod-mediated light sensitivity, in aging and early AMD. RMDA is not only more likely to be slower in eyes with early AMD compared to eyes in normal macular health, but also delayed RMDA is a functional biomarker (i.e., risk factor) for incident early AMD. The next frontier is to establish the structural basis of rod-mediated dysfunction in older adults at-risk for AMD and those already converted to early AMD. Our unifying hypothesis across all aims is: Early AMD is a disease of micronutrient deficiency and vascular insufficiency, due to detectable structural changes in the retinoid re-supply route from the choriocapillaris to the photoreceptors, manifest functionally as delayed rod- mediated dark adaptation. These structural disturbances will occur in specific chorioretinal layers and regions reflecting the spatial distribution of disease in the photoreceptor support system. Our multidisciplinary team has expertise in visual psychophysics, epidemiology, histopathology, digital image analysis and interpretation for retinal disease, study design, and biostatistics. Toward our goals, we will execute the 3 specific aims in an exceptionally well phenotyped cohort at aging-early AMD transition, staged by the AREDS 9-step scale, with 3 years of longitudinal follow-up: (1) To examine the abundance and extent of AMD's pathognomonic deposits (drusen and newly recognized subretinal drusenoid deposits) in relationship to scotopic dysfunction via optical coherence tomography (OCT); (2) To examine RPE cell bodies as structural correlates of scotopic dysfunction via quantitative fundus autofluorescence and layer thicknesses via OCT; (3) To measure vascular density (coverage of macular Bruch's membrane by choriocapillaris), a measure of exchange capacity for outer retinal cells, using OCT angiography. An accurate map and timeline of structure-function relationships in aging and early AMD gained from our research, especially the critical transition from aging to disease, will help define major effects that can be developed into future treatments and preventative measures. Our data will help define new endpoints for clinical trials for drugs to treat early AMD, the absence of which has impeded translational research on this prevalent cause of legal blindness. Endpoints are needed more than ever, because causal treatments targeting lipids in drusen and BrM can be pressed forward, thanks to clinical and pre-clinical proof- of-concept studies.